Integrase Inhibitoren AREVIR-GenaFor-Meeting Bonn, 10.-11. April 2008 Dr. med. Stefan Esser Universitätshautklinik Essen
Die zweite Welle antiretroviral wirksamer Substanzen Wamsley S, 15th CROI 2008 Boston USA
The second HAART-Wave: Neue Substanzen und Klassen Neue Substanzen und Klassen HIV HIV gp41 gp41 gp120 gp120 provirale provirale virale virale DNA DNA RNA RNA Entry- Reverse Entry- Transkriptase/ Maturations Maturations Inhibitoren: Inhibitoren: Ribonuklease H Integrase (Reifungs) (Reifungs) - Attachment - Attachment Inhibitoren Inhibitoren: - CCR5: Inhibitoren - CCR5: *Maraviroc *Raltegravir *Maraviroc *Vicriviroc *Elvitegravir *Vicriviroc Integrase Protease - CXCR4 virale - CXCR4 virale Proteine - Fusionsinhibitor Proteine - Fusionsinhibitor Nukleus Reverse Reverse Transkriptase Transkriptase CD4-T-Lymphozyt Inhibitoren: Protease Inhibitoren: Protease -NRTI Inhibitoren: -NRTI Inhibitoren: mRNA -NNRTI: Etravirine mRNA -NNRTI: Etravirine -Darunavir zelluläre -Darunavir zelluläre -Tipranavir DNA -Tipranavir DNA Universitätshautklinik Essen
HIV-Integrase 2 In-Dependent Virale DNA Synthesis Inhibitoren Processing of 3´Ends 1 Nuclear Assembly on Viral Entry DNA in a Nuclear Membrane Nucleoprotein Complex 3a Target 3 DNA Strand- Binding = Transfer Gap Repair HIV-1 Integrase Inhibitoren 3b Strand Transfer Inhibitoren = MK-0518 Concerted Gap Repair Target DNA Cleavage and Joining Mature Provirus Universitätshautklinik Essen
Universitätshautklinik Essen
Raltegravir (RAL) with TDF and 3TC in treatment-naive patients HIV RNA <50 c/mL (95% CI) [NC=F] � Patients randomized equally to TDF/3TC + 100 HIV RNA <50 c/mL (%) EFV or RAL at 100, 200, 400 or 600 mg BID 80 Patients with – Mean HIV RNA 4.6–4.8 log 10 c/mL 60 – Mean CD4+ 271–338 cells/mm 3 40 20 – All susceptible at baseline 0 � AEs similar 0 2 4 8 12 16 24 32 40 48 Week RAL100 mg BID (n=39) RAL 400 mg BID (n=41) – More CNS AEs with EFV RAL 200 mg BID (n=40) RAL 600 mg BID (n=40) EFV 600 mg QD (n=38) Change from baseline Virologic failures 60 � RAL, n=5 (3%) 50 RAL EFV – Two with integrase mutations; both 40 N155H, 1 with multiple mutations 30 Mg/dL – 3TC resistance (n=4) 20 – K65R (n=1) 10 � EFV, n=1 (3%) 0 TC LDL TG TC:HDL – K65R and G190E -10 -20 Universitätshautklinik Essen Markowitz M, et al. 4th IAS , Sydney 2007, #TUAB104
BENCHMRK-1 & -2: Raltegravir in Treatment-Experienced Patients Current Analysis: Planned follow-up: Week 48 Week 156 Raltegravir 400 mg twice daily + OBR* HIV-infected patients with (BENCHMRK-1: n = 232; triple-class resistance and BENCHMRK-2: n = 230) HIV-1 RNA > 1000 copies/mL Placebo + OBR* (BENCHMRK-1: N = 352; (BENCHMRK-1: n = 118; BENCHMRK-2: N = 351) BENCHMRK-2: n = 119) *Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted. 1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789. Universitätshautklinik Essen
Patient Characteristics: BENCHMRK-1 Raltegravir + OBT Placebo + OBT N = 232 N = 118 Mean Age, yrs (SD) 46 (9) 44 (8) % Male 84 87 % Caucasian 75 81 Median CD4 Count, cells/mm 3 140 105 GM Viral Load, copies/mL (log 10 HIV RNA) 40519 (4.6) 31828 (4.5) %with AIDS 94 89 Median yrs of prior ARTs (Mean # ART) 11 (12) 10 (12) % Hepatitis B+ / % Hepatitis C+ / both 6 / 13 / 2 3 / 19 / 2 % GSS † 0 / 1 30 / 33 29 / 41 % PSS † 0 / 1 19 / 29 18 / 33 % new enfuvirtide in OBT 21 20 % new darunavir in OBT 27 25 † GSS/PSS = total ART in OBT to which patient's virus showed geno/phenotypic sensitivity by Phenosense GT assay. Enfuvirtide and darunavir use in naïve patients were each counted at +1 active agent and added to GSS/PSS. Universitätshautklinik Essen
Patient Disposition: BENCHMRK-1 Raltegravir + OBT Placebo + OBT N (%) N (%) Randomized 234 118 Treated 232 (99) 118 (100) Continuing in Double-Blind phase 193 (83) 50 (42) Entered Open-Label post VF* phase 33 (14) 60 (51) Discontinued study 6 (3) 8 (7) Discontinued due to adverse event 4 (2) 4 (3) * Definition of virologic failure: 1) <1 log 10 ↓ HIV RNA from baseline and HIV RNA >400 copies/mL at wk 16, OR 2) virologic relapse: >1 log 10 ↑ HIV RNA above nadir or >400 copies/mL from nadir after response <400 copies/mL(on 2 consecutive measurements at least 1 week apart). Universitätshautklinik Essen
Change From Baseline in CD4 Cell Count (cells/mm 3 ) and Log 10 HIV RNA (BENCHMRK-1, Observed Failure Approach) •150 120 •CD4 Cell Count (cells/mm ) •Change from Baseline •125 83 •100 p<0.001 •75 p<0.001 •50 •25 49 31 •3 •) •mL •0 •0 •Change from Baseline •10 •Copies/ -0.7 -0.8 •- •1 p<0.001 p<0.001 •HIV RNA (log •- •2 -1.7 -1.9 •- •3 •0 •2 •4 •8 •12 •16 •24 •32 •40 •48 •Weeks •Number of Contributing Patients •Raltegravir •* •232 •227 •218 •218 •218 •222 •(CD4) •Placebo* •118 •112 •114 •114 •114 •114 •Raltegravir •* •232 •224 •226 •224 •226 •227 •(RNA) •Placebo* •118 •113 •114 •113 •114 •114 •* +OBT •Note: Baseline carried forward for •virologic •failures. •p<0.001 at Week 16 and Week 48 for both parameters. Note: Baseline carried forward for virologic failures. For change from baseline in CD4 cell counts, p-value was derived from a mixed-effects model adjusted for: baseline CD4 cell count, stratum, treatment, visit, interactions between visit and previous variables. For change from baseline in log 10 HIV RNA level, p-value was derived from a parametric regression model adjusted for: baseline HIV RNA level(log 10 ), first enfuvirtide use in OBT, first darunavir use in OBT and active PI in OBT.
Percent of Patients Achieving HIV RNA <50 Copies/mL(95% CI) (BENCHMRK-1, Non-Completer=Failure Approach) 100 HIV RNA <50 Copies/mL Percent of Patients with 80 65% 62% 60 p<0.001 p<0.001 40 33% 20 31% 0 0 2 4 8 12 16 24 32 40 48 Weeks Number of Contributing Patients Raltegravir* 232 231 231 230 229 232 229 230 231 Placebo* 118 118 118 118 117 118 118 118 118 * +OBT; p-value was derived from a logistic regression model adjusted for baseline HIV RNA level (log 10 ), first enfuvirtide use in OBT, first darunavir use in OBT, active PI in OBT. At Week 48, HIV RNA <400 copies/mL was achieved in 74% of the raltegravir group vs 36% of the placebo group (p<0.001)
Summary of Clinical Adverse Events (AEs) in BENCHMRK-1 Raltegravir+OBT Placebo+OBT (N=232) (N=118) Difference from Placebo † % % % (95% CI) p-Value Mean follow-up (weeks) 54.5 38.6 % patients with: Any AE 90.9 84.7 6.20 (-0.7, 14.4) 0.105 Drug-related ‡ AE 48.7 54.2 -5.53 (-16.4, 5.6) 0.366 Serious AE 19.8 17.8 2.03 (-7.1, 10.2) 0.774 Serious drug-related AE 3.0 0.8 2.17 (-1.8, 5.4) 0.275 Deaths 1.3 2.5 -1.25 (-6.0, 1.7) 0.409 Discontinued due to AE 1.7 3.4 -1.67 (-6.8, 1.6) nps § † Tests of significance were performed on the percentage of patients with at least one adverse event in the category. The 95% CIs were calculated using Miettinen and Nurminen's method. p-Values were generated using the Fisher exact test. ‡ Determined by the investigator to be possibly, probably, or definitely drug related. § nps=not pre-specified for statistical analysis. Universitätshautklinik Essen
Percent of Patients with Drug Related ‡ Clinical Adverse Events ( ≥ 2%, any intensity) in BENCHMRK-1 Raltegravir+OBT Placebo+OBT (N = 232) (N = 118) Mean Follow-Up (weeks) 54.5 38.6 % Patients With: Abdominal Distension 0.4 3.4 Abdominal Pain 1.3 3.4 Diarrhoea 6.9 14.4 Nausea 3.9 6.8 Vomiting 2.6 7.6 Fatigue 2.2 0 Injection Site Nodule 0.4 2.5 Injection Site Pain 2.6 1.7 Injection Site Reaction 7.3 11.9 Arthralgia 2.2 0 Headache 3.0 6.8 Insomnia 1.7 3.4 Lipodystrophy Acquired 1.7 3.4 Pruritus 2.2 0 Subcutaneous Nodule 1.7 2.5 ‡ Determined by the investigator to be possibly, probably, or definitely related to any drug in the treatment regimen.
Percent of Patients with Grade 3 or Grade 4 Laboratory Abnormalities in BENCHMRK-1 Laboratory Test (Unit) Toxicity Criteria* Raltegravir Placebo (N=232) (N=118) ANC (10 3 /µl) Grade 3 0.50 -0.749 2.6 2.5 Grade 4 <0.50 0.9 0 Hemoglobin (gm/dL) Grade 3 6.5 -7.4 1.3 0.8 Grade 4 <6.5 0.4 0 Platelet count (10 3 /µL) Grade 3 25 – 49.999 0.9 0.8 Grade 4 <25 1.7 0.8 ≥ 190 Fasting LDL-C (mg/dL) Grade 3 7.8 6.4 Fasting cholesterol (mg/dL) Grade 3 >300 11.6 4.2 Fasting triglyceride (mg/dL) Grade 3 751 - 1200 4.3 1.7 Grade 4 >1200 3.0 0.8 Grade 3 251 - 500 1.7 1.7 Fasting glucose (mg/dL) Grade 4 >500 0 0 Serum creatinine (mg/dL) Grade 3 1.9 – 3.4 x ULN 0 0 ≥ 3.5 x ULN Grade 4 0 0 * Grades 3 and 4 per DAIDS toxicity criteria. Universitätshautklinik Essen
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